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Haem > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

State the steps involved in haemostatic plug formation from the time of injury.

A

Vessel constriction

Formation of an unstable platelet plug (platelet adhesion + platelet aggregation)

Stabilisation of plug with fibrin (blood coagulation)

Dissolution of clot and vessel repair (fibrinolysis)

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2
Q

What comprises a normal vessel wall?

A

Endothelial Cells - anticoagulant barrier (TM, EPCR, TFPI, GAG)

Subendothelium- procoagulant

Basement Membrane - (Elastin, Collagen)

Vascular smooth muscle cells - (tissue factor)

Fibroblasts - (Tissue factor)

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3
Q

What component found underneath the endothelium is involved in triggering the coagulation cascade?

A

Procoagulant subendothelial structures e.g. collagen Tissue factor is also expressed on the surface of the cell that underlie blood vessels but it is NOT normally expressed within the circulation itself

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4
Q

State some important factors produced by endothelial cells.

A

Prostacyclin
Thrombomodulin
Von Willebrand Factor
Plasminogen Activator

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5
Q

How are platelets formed? What are their properties?

A

Derived from megakaryocytes (from bone marrow or lungs) 4000 platelets to 1 megakaryocyte produced via granulation

Platelet properties:
2-4 micrometers 
Anuclear 
10 day lifespan 
150-350 x109/L
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6
Q

Describe the ultrastructure of platelets.

A
  • Highly complex although anuclear
  • Many surface receptor (e.g GPVI, GPIb/V/IX, AiibB3, A2B1) Receptors are responsive to agonists present in tissue damage
  • Turn from quiescent to active form when triggered
  • Granules within platelet (Growth factors, fibrinogen, FV, VWF) various coagulative factors
  • Dense granules (ADP, ATP, Serotonin, Ca2+) Enhance action of neighbouring platelets bind to AiibB3 and GPiib/iiia
  • Phospholid membrane - Inverted in active platelet, gains negative charge recruits clotting factors
  • Cytoskeleton - (microtubules and actomysin) allow significant changes of cell shape
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7
Q

Describe other platelet roles aside from thrombosis.

A

Cancer (metastasis)
Atherosclerosis
Infection
Inflammation

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8
Q

Describe the process of platelets binding to vWF or directly to collagen.

A

Multimeric VWF circulates in plasma with platelets however in globular form platelet bindings sites are not available for binding In vessel injury endothelium matrix protein exposed (mostly collagen) VWF binds to collagen and unravelled by shear force of flowing blood
Platelet binding sites revealed by this and platelets recruited, Bind to Gp1b (glycoprotein one B)

At low shear force (not in arteries or capilleries) platelets can also bind to collagen via GPVI and alpha2beta1 receptors Therefore VWF less important in venous system

NOTE: THROMBIN CAN ALSO ACTIVE PLATELETS

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9
Q

What happens following the passive adhesion of platelets and engagement of receptors?

A

The receptors signal inside the cell to release ADP from the storage granules and to synthesise thromboxane These bind to receptors on the surface of the platelets and activate them

Once activated, GlpIIb/IIIa receptors become available, which can bind to fibrinogen and allows the platelets to aggregate

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10
Q

Which receptors on the platelets become available following activation of the platelets and what do they bind to?

A

GlpIIb/IIIa

These bind to fibrinogen

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11
Q

How do platelets stick to each other?

A

AiibB3 recptor is an intergrin which upon activation cross-links platelets and binds to fibrinogen

Multiple layers of this form early plug

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12
Q

How do platelets change shape during adhesion?

A

Flowing disc shape -> rolling ball-shape -> hemisphere-shape (reversable adhesion) -> spreading (irreversable)

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13
Q

The platelet count is an important test for monitoring platelet function. How are the results interpreted?

A

<100x109/L no spontaneous bleeding, bleeding with trauma
<40x109/L Spontaneous bleeding commonly occurs
<10x109/L Severe spontaneous bleeding

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14
Q

Where is von Willebrand factor produced?

A

Endothelial cells and a little bit by megakaryocytes

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15
Q

What factors do megakaryocytes produce?

A

Factor V

Von Willebrand Factor

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16
Q

Which clotting factors contain Gla domains?

A

Prothrombin (F2)
F7
F9
F10

17
Q

How do Gla domains function?

A

Gla domains allow binding to negatively charged phospholid surface - domain formation is dependant on vitamin K

Contain 2 COOH groups that bind it to many Ca2+ ions, causing them to develop into shape for binding membranes

18
Q

What anti-clotting agent targets Gla domain factors?

A

Warfarin is vitamin K antagonist.

Inhibits vitamin K epoxide reductase thus inhibiting the gamma carboxylation of factors 2, 7, 9 and 10

19
Q

What are the events of the clotting cascade via the extrinsic pathway?

A

Vessel damage exposes TF (only procoagulant factor not requiring protelytic activation) produced by cells

TF binds to FVII forming FVIIa and binds cell surfaces via Gla domain

TF-FVIIa complex proteolytically activates FIX and FX to FIXa and FXa

FXa converts prothrombin to thrombin (VERY INEFFICIENT)

Thrombin cleaves FVIII to FVIIIa and FV to FVa

FVIIIa activates more FIXa

FVIIIa-FIXa complex activates far more FXa

FVa joins to FXa, FXa-FVa complex converts far more (x300,000) prothrombin to thrombin

Thrombin convert fibrinogen to fibrin - supports plug.

20
Q

Where is more TF expressed?

A

TF expressed more in organs where higher risk associated with extravascular bleed (e.g Lung, brain, heart, testis, uterus and placenta)

21
Q

What is the structure of FVII?

A

FVII - serine protease zygomen, with a serine protease domain, 2 EGF-like domains and a Gla domain

FVII, FIX, FX and protein C have same domain structures

22
Q

What are the endogenous inhibitors of the clotting cascade?

A

TFPI - tissue factor pathway inhibitor
APC and protein S
AT - Anti-thrombin

23
Q

How does TFPI pathway work?

A

TFPI - targets initiation step. K2 domain of TFPI binds to FXa which re-associates with TF-FVIIa complex - none of these proteins can now propagate thrombosis any further.

K1 domain inactivates the active site of TF-FVIIa complex

(LOW TFPI IN BLOOD)

24
Q

How does the protein C pathway work?

A

Protein C - activated by thrombin-Thrombomodulin complex on endothelial cells. Activated Protein C (APC) proteolytically inactivates FVa and FVIIIa cofactors (Protein S acts as a cofactor for protein C)

Note: Thrombin-TM complex cannot activate fibrinogen any longer

25
Q

Which of the clotting factors are serine proteases?

A 
thrombin
FIXa
FXa
FXIa
FXIIa

(Serine proteases all contain catalytic triad His/Asp/Ser
Cleave substrate after specifc Arg (and Lys) residues)

26
Q

How does the anti-thrombin pathway work?

A

Anti-thrombin - Serine protease inhibitor (SERPIN) Inactivates Serine proteases: FXa, thrombin, FIXa, FXIa, ‘mops up’ Serine proteases that escape point of vessel damage

Heparin binds to AT to increase efficiency (Heparin is used for immediate anticoagulation in venous thrombosis and pulmonary embolism)

27
Q

How does anti-thrombin inactive serine proteases?

A

Anti-thrombin has a reactive loop that irreversibly inhibits the active site on the clotting factors So anti-thrombin acts as a scavenger in stopping inappropriate action of clotting factors

28
Q

How does heparin potentiate anti-thrombin?

A

Heparin is a linear negatively charged polysaccharide Once bound to anti-thrombin it changes the position of the reactive loop and makes the inhibition occur faster When inhibiting factor 10a, a relatively SHORT chain of heparin is sufficient (low molecular weight heparin) When inhibiting thrombin, you require a LARGE chain (standard/unfractionated heparin)

NOTE: standard/unfractionated heparin inhibits either Factor 10a or thrombin

29
Q

What two proteins assemble on the surface of a clot to allow fibrinolysis to take place? Where are these proteins made?

A

Plasminogen
Tissue Plasminogen Activator (tPA)

Plasminogen is a plasma protein tPA is produced by endothelial cells

30
Q

What is produced from the break down of the fibrin clot and how does this level change in DIC?

A

Fibrin degradation products (FDP)

This is elevated in DIC

31
Q

What factors are used in therapeutic thrombolysis of myocardial infarction?

A

tPA and bacterial activator

streptokinase

Haem (11 decks)

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